Effects of cytochrome P450 family 3 subfamily a member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia

Abstract

The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A5∗3. PCR was then used to express the mRNA expression of CYP3A5. A midazolam probe method was used to detect CYP3A enzyme activity, and DNR concentrations were measured using high performance liquid chromatography. Children with different genotypes had different mRNA expression levels of CYP3A5, and CYP3A enzyme activity in children with the CYP3A51 allele was higher, compared with that in children with the CYP3A5∗3 allele. In addition, the area under the curve (AUC)0-24 h and AUC0-∞ of DNR were significantly different in children with different genotypes, however, no statistically significant differences were found in half-life or maximum concentration. The AUC of DNR was increased in children with acute lymphatic leukemia who suffered from cardiotoxicity, compared with those in the normal group. The CYP3A5∗3 gene polymorphism was closely associated with the mRNA expression of CYP3A5, CYP3A enzyme activity and DNR plasma drug concentration, and exhibited different drug adverse reactions.